This pilot research investigates and develops novel reconstruction methods and imaging strategies to reveal and materialize so-far unrecognized and untapped benefits of time-of-flight positron emission tomography (TOF-PET) imaging. PET is a quantitative molecular imaging technology that has proved value in cancer-related clinic and research. PET images often yield information that leads to better diagnosis of cancers and results in significant changes to cancer treatment and management. In research, it is a powerful tool for studying the initiation and growth mechanisms of cancers and for evaluating, in vivo, the effects of drugs and treatments. Making improvements to PET imaging performance therefore has great significance to cancer research, diagnosis, cure and management. The ability of TOF-PET imaging to substantially improve the quality and quantification of PET images is well known. However, our recent theoretical discovery reveals that the full benefits of TOF-PET imaging have yet to be realized and materialized. This research aims to change this situation and bring out the full potentials of TOF-PET imaging, hence enhancing the already important role of PET imaging in cancer research and clinic. This proposed research has five specific aims for making contributions to five knowledge domains: (1) to develop new reconstruction theories and methods for TOF-PET;(2) to acquire new understandings about the characteristic distributions of the trues, scatter and randoms in the TOF-PET measurement space;(3) to develop, by utilizing the new methods and knowledge obtained in the above aims, new imaging strategies for improving the detection of lesions in the brain and lung;(4) to study new tradeoffs in PET system design that are created by the new methods and knowledge obtained in the above aims;and (5) to develop new methods for creating volume renderings of the image function under study directly from the TOF-PET data, bypassing image reconstruction. This pilot research meets in time with the re-invigorated developments of TOF-PET instruments that are being conducted by other researchers to provide new methods, understandings, imaging strategies, and information for unveiling and materializing the untapped benefits of TOF-PET imaging. The research results can advance PET imaging technology further by bringing out the full potentials of TOF-PET imaging and creating new choices and flexibilities in data utilization, imaging strategies and system design. PUBLIC HEALTH RELEVANCE: It is well known that high-quality PET images of a patient can considerably improve cancer detection and diagnosis, consequently leading to better cure and management of this devastating disease. PET imaging also has proved value in cancer research, such as for studying the initiation and growth mechanisms of the disease and for developing personalized treatments. This proposed research will create new knowledge, reconstruction methods, and imaging strategies that can significantly improve the quality of current PET imaging and, therefore, increase the value of PET imaging in cancer research, diagnosis, cure and management.